5-78780649-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000046.5(ARSB):ā€‹c.1350G>Cā€‹(p.Trp450Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

ARSB
NM_000046.5 missense

Scores

13
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.63
Variant links:
Genes affected
ARSB (HGNC:714): (arylsulfatase B) Arylsulfatase B encoded by this gene belongs to the sulfatase family. The arylsulfatase B homodimer hydrolyzes sulfate groups of N-Acetyl-D-galactosamine, chondriotin sulfate, and dermatan sulfate. The protein is targeted to the lysozyme. Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2016]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 5-78780649-C-G is Pathogenic according to our data. Variant chr5-78780649-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARSBNM_000046.5 linkuse as main transcriptc.1350G>C p.Trp450Cys missense_variant 8/8 ENST00000264914.10 NP_000037.2
ARSBXM_011543390.2 linkuse as main transcriptc.1350G>C p.Trp450Cys missense_variant 9/9 XP_011541692.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARSBENST00000264914.10 linkuse as main transcriptc.1350G>C p.Trp450Cys missense_variant 8/81 NM_000046.5 ENSP00000264914 P1P15848-1
ARSBENST00000521011.1 linkuse as main transcriptn.315G>C non_coding_transcript_exon_variant 3/33

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152060
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251286
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135816
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461798
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:4
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 06, 2023- -
Likely pathogenic, no assertion criteria providedclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
Likely pathogenic, criteria provided, single submittercurationLaboratory of Diagnosis and Therapy of Lysosomal Disorders, University of PadovaJan 01, 2018In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 29, 2023For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ARSB function (PMID: 27826022). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function. ClinVar contains an entry for this variant (Variation ID: 559708). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 27826022). This variant is present in population databases (rs555785323, gnomAD 0.007%). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 450 of the ARSB protein (p.Trp450Cys). -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 23, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.88
D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-11
D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0070
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.80
Gain of loop (P = 0.1069);
MVP
1.0
MPC
1.1
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs555785323; hg19: chr5-78076472; API